Diabetes is generally characterized by relatively high levels of plasma glucose (hyperglycemia) in the fasting state. Patients having type 2 diabetes (non-insulin dependent diabetes mellitus (NIDDM)) produce insulin (and even exhibit hyperinsulinemia), whilst demonstrating hyperglycemia.
Type 2 diabetics can often develop insulin resistance, in which the effect of insulin in stimulating glucose and lipid metabolism is diminished. Further, patients having insulin resistance, but have not developed type 2 diabetes, are also at risk of developing Syndrome X (metabolic syndrome). Syndrome X is characterized by insulin resistance, along with obesity (e.g., abdominal obesity), hyperinsulinemia, high blood pressure, relatively low HDL and relatively high VLDL.
Glucocorticoids (e.g., cortisol in humans, corticosterone in rodents) are counter regulatory hormones that oppose the action of insulin. It is established that glucocorticoid activity is controlled at the tissue level by intracellular interconversion of active cortisol and inactive cortisone by the 11-beta hydroxysteroid dehydrogenases, 11βHSD1, which activates cortisone and 11βHSD2, which inactivates cortisol. Excess levels of glucocorticoids (e.g., cortisol) can cause metabolic complications. For example, excess cortisol is associated with disorders including NIDDM, obesity, dyslipidemia, insulin resistance, and hypertension.
It is believed that inhibition of 11βHSD1 can reduce the effects of excessive amounts of 11β-hydroxysteroids, e.g., cortisol, and therefore can be useful for the treatment and control of diseases mediated by abnormally high levels of cortisol and other 11β-hydroxysteroids, e.g., NIDDM, obesity, dyslipidemia, and hypertension.